These studies are designed to establish directly the relative contributions of the brain and liver to the production of tolerance to barbiturates by determining systematically: a) whether the administration of barbiturates directly into the CNS will produce tolerance; b) whether the tolerance produced is accompanied by changes in the activity of the hepatic drug-metabolizing enzymes; c) whether the induction of the hepatic drug-metabolizing enzymes by systemic administration of barbiturates modifies the effects to centrally administered drugs; d) and whether the administration of protein and nucleic acid synthesis inhibitors into the CNS affects the production of tolerance to barbiturates. In addition, the distribution of the drug in the brain subfractions will be examined after systemic and intraventricular administration of the barbiturates into naive and tolerant rats. We propose: a) to determine the dose-response relationship for the production of sleep in both tolerant and naive animals by the intraventricular administration of a) barbiturates; b) to induce the hepatic drug-metabolizing enzymes by chronic oral administration of phenobarbital and re-examine the dose-response as described above; c) to study the effects of inhibiting protein synthesis in the brain (e.g., by direct central injections of actinomycin D and cycloheximide) on tolerance development; and d) to establish the cellular and molecular localization of barbiturates in the brains of tolerant and non-tolerant animals by employing the isotopically labeled drugs.